Both genetic and environmental factors modulate the effects of alcohol on the liver. For instance, the consequences of alcohol abuse vary between ethnic groups, and patients with steatosis are sensitized to alcohol induced liver damage. Both alcohol and lipid accumulation induce oxidative stress in hepatocytes, and it is hypothesized that through the induction of oxidative stress and the resultant endoplasmic reticulum (ER) stress, alcohol potentiates damage in fatty livers. However, the genes that participate in this process are not well defined. Zebrafish are a widely used vertebrate model, and the availability of mutants and morpholinos to knock-down target genes in embryos is an excellent system for determining the genetic contribution to developmental and physiologic processes. Previous work suggests that ethanol treatment of early stage zebrafish embryos results in phenotypes similar to those of the fetal alcohol syndrome. Antioxidant treatment partially abrogates these teratogenic effects, suggesting that, as in mammals, oxidative stress is a central mechanism by which alcohol causes cellular damage in zebrafish embryos. The zebrafish liver is mature by days 4-5 of development, and our preliminary results show that treating these late stage embryos with 1-2% ethanol causes hepatomegaly and steatosis. Additionally, cyp2e1, markers of oxidative and endoplasmic reticulum (ER) stress, and genes involved in cholesterol biogenesis are upregulated by ethanol in a dose-dependent manner. Thus zebrafish provide a novel model system to investigate the genetic basis for liver damage induced by alcohol, and will allow inquiry into the role of oxidative stress. Furthermore, homozygous mutation of the novel gene foie gras (fgr) results in molecular and histological features of fatty liver disease on day 5 of development, including signs of decreased hepatic function, liver injury, and ER stress in hepatocytes, followed by embryonic death on day 7. Our data demonstrate that fgr embryos are sensitized to alcohol toxicity and fgr+/- adults, while viable and fertile, are sensitized to hepatic injury. We will use this model to investigate the genetic basis for alcohol-induced damage of steatotic livers. Specific aims are: 1. To develop an alcohol induced liver injury model in zebrafish embryos. 2. Identify genetic modifiers of alcohol induced liver damage in zebrafish. 3. To investigate the interaction between steatosis, oxidative stress, and liver damage in the fgr model of fatty liver disease.